The association between maternal methylenetetrahydrofolate reductase C677T and A1298C polymorphism and birth defects and adverse pregnancy outcomes

Published studies indicate the MTHFR C677T and A1298C polymorphisms are associated with abnormal homocysteine levels, which may cause various pregnancy complications and birth defects. However, the results obtained from different studies have been inconsistent. Therefore, this meta‐analysis explores the association between MTHFR polymorphisms and birth defects and adverse pregnancy outcomes. The PubMed, ScienceDirect, Embase, and China Biology Medicine literature databases and ClinicalTrials were searched. Analyses of public bias, meta‐regression, subgroups, and sensitivity were used to ensure the robustness of our results. MTHFR C677T was significantly associated with recurrent pregnancy loss in developing countries (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.20‐1.50) but not in developed countries (OR, 0.87; 95% CI, 0.68‐1.11). No significant relationship was found between MTHFR A1298C and recurrent pregnancy loss (OR, 1.04; 95% CI, 0.93‐1.18). MTHFR C677T and A1298C were not associated with preeclampsia (OR, 1.06; 95% CI, 0.97‐1.16 and OR, 1.16; 95% CI, 0.97‐1.39, respectively), and C677T was not associated with placental abruption (OR, 1.03; 95% CI, 0.87‐1.21), intrauterine growth retardation (OR, 1.02; 95% CI, 0.90‐1.15), or congenital heart disease (OR, 1.05; 95% CI, 0.89‐1.25). MTHFR C677T, but not A1298C, was associated with neural tube defects (OR, 1.24; 95% CI, 1.08‐1.42) and Down syndrome (OR, 1.65; 95% CI, 1.39‐1.95). Conclusion Although MTHFR C677T and A1298C are significantly associated with some types of congenital defects and adverse pregnancy outcomes, the impact of these polymorphisms is moderate. What's already known about this topic? The MTHFR C677T and A1298C polymorphisms, leading to protein dysfunction, are associated with abnormal homocysteine levels. However, the relationship with adverse pregnancy outcomes and birth defects is unclear. What does this study add? From the present study, we have found that (1) MTHFR C677T mutation is associated with RPL in developing but not developed countries and with NTD and DS and (2) the impact of such associations is moderate.